Inflammatory bowel disease (IBD) comprising Crohn's disease and ulcerative colitis, has been estimated to afflict more than 2 million Americans. Unfortunately, a permanent cure of these IBD and related diseases has not been found. However, certain treatments, when properly utilized, will substantially reduce the symptoms thereof. Among these preferred treatments for IBD are preparations containing 5-ASA, and/or its precursor molecules, which may be molecularly split by the intestinal flora to produce in situ the 5-ASA treatment molecule.
Various means of carrying and administering effective medicants ultimately to the afflicted bowel areas have been developed, and include, inter alia, oral administration, suppositories, and enemas, for example. However, each of these delivery methodologies have had certain disadvantages and/or deficiencies associated therewith.
For example, oral administration of the 5-ASA molecule, usually in solid form, generally may require a higher dosage of the 5-ASA active agent, because of the effect of gastric juices thereon as the oral dosage passes through the digestive process. In order to reduce the negative influence of gastric juices upon oral doses, such orally administered medicants generally have been enterically coated, and/or have been delivered by an enteric feeding tube. Examples of oral dosage systems utilizing 5-ASA treatment include U.S. Pat. No. 2,647,853 to Lardé et al., U.S. Pat. No. 4,540,685 to Bauer, U.S. Pat. No. 4,632,921 to Bauer, U.S. Pat. No. 4,699,902 to Bauer, U.S. Pat. No. 5,120,306 to Gosselin, United States Publication No. 2006/0223787 A1 to Devane et al., United States Publication No. 2006/0264409 A1 to Harty, United States Publication No. 2007/0043004 A1 to Jepsen, and United States Publication No. 2007/0066578 A1 to Shimizu.
Suppository utilizations of 5-ASA have generally utilized 5-ASA in the solid form, or in greatly concentrated form for containment within a dissolvable suppository as inserted into the rectum. However, given the relatively low volume of such a suppository, sufficient spreading of the 5-ASA active agent to the areas of the bowel afflicted by IBD has been a continuing problem with the suppository methodology. Examples of the suppository treatment vehicle for 5-ASA include U.S. Pat. No. 4,540,685 to Bauer, U.S. Pat. No. 4,632,921 to Bauer, U.S. Pat. No. 4,699,902 to Bauer, U.S. Pat. No. 5,449,520 to Frigerio et al., and U.S. Pat. No. 5,082,651 to Healey et al.
Generally speaking, enema formats for treatment of inflammatory bowel diseases have had the substantial utility of possessing the ability to deliver a substantial volume of 5-ASA as contained within a treatment vehicle and with such application directly to the areas of the bowel afflicted by IBD. Such enemas have included foam enemas and liquid enemas. As for foam enemas, the disadvantage of a relatively low density of the foam necessarily results in difficulties of administering substantial and accordingly therapeutic amounts of the 5-ASA active agent to the appropriate portions of the bowel requiring treatment. Indeed, foam enemas have long experienced difficulties in penetrating all areas of the bowel, including such areas as the ascending colon. Certain foam references include U.S. Pat. No. 5,725,872 to Stamm et al., U.S. Pat. No. 5,449,520 to Frigerio et al., U.S. Pat. No. 5,082,651 to Healey et al., and European Patent No. 1312368 to Kühn.
Hence, the liquid enema format possesses certain advantages not present in oral treatment, suppositories, or foam enemas, in that liquid enemas have simultaneously both sufficient volume and density for the required penetration to the entirety of the bowel, and thus facilitate treatment of the entirety thereof. One example of liquid enemas having substantial medical and commercial success are those disclosed and described in U.S. Pat. No. 4,657,900 to Powell et al., issued on Apr. 14, 1987, and entitled “Pharmaceutical Article of Manufacturer Comprising a Bi-Sulfite Stabilized Aqueous Solution of 5-Amino Salicylic Acid and Method”, and owned in common with the assignee hereof. The 5-ASA compositions set forth in U.S. Pat. No. 4,657,900 to Powell et al. have been marketed under the trademark Rowasa® by Solvay Corporation and the assignee hereof, and of which the present invention constitutes a substantial improvement thereover. Accordingly, the teachings of U.S. Pat. No. 4,657,900 to Powell et al., are incorporated by reference herein.
As set forth in the Powell et al. patent, the enema compositions thereof are stabilized against oxidation (and thus decomposition, discoloration and reduction in efficacy) of the 5-ASA active agent by the inclusion of sulfite compounds (i.e., bisulfites, metabisulfites, etc.), which provide the enema composition with a substantial shelf-life upon prolonged storage. However, certain disadvantages, and in particular colon/bowel irritation, have been associated with such stabilizing sulfite compounds. Accordingly, the reduction and/or elimination of bowel irritating compounds, such as, for example, sulfite compounds and/or other antioxidants for the 5-ASA active agent, that albeit are necessary for stabilization, has been long since deemed beneficial, but until the present invention has not been successfully accomplished.
One example of attempts to compete with the present assignee's prior Rowasa® commercial embodiment of the compositions and methods set forth in U.S. Pat. No. 4,657,900 to Powell et al., has been enemas produced and distributed by Teva Pharmaceuticals USA of Sellersville, Pa. 18960, and constitutes a liquid enema product (FDA approved in 2004) for the treatment of IBD. However, the Teva Liquid Enema 5-ASA product, as approved approximately 17 years after the issuance of the Powell et al. patent, continues to contain the bowel irritating bisulfite stabilizer. The Teva product insert is dated “Revised: 11/2006” and states in regard to the bisulfite compounds:
“WARNINGS Mesalamine rectal suspension USP contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low. Sulfite sensitivity is seen more frequently in asthmatic or in atopic nonasthmatic persons. Epinephrine is the preferred treatment for serious allergic or emergency situations even though epinephrine injection contains sodium or potassium metabisulfite with the above-mentioned potential liabilities. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in epinephrine injection should not deter the administration of the drug for treatment of serious allergic or other emergency situations.”
Accordingly, and as recognized by the competitors in the relevant art marketplace, reduction in bowel irritating stabilizers/anti-oxidants for the 5-ASA active ingredient, such as, for example, potassium metabisulfite, has been desirable for an extended period of time comprising at least 20 years, but has not been successfully accomplished until the present invention.
Therefore, it is readily apparent that there is a need for enema compositions and methods for treating inflammation of the large intestine, in particular the rectum, sigmoid colon, and the descending colon, that avoids the side effects associated with the bowel irritating sulfite compounds and other antioxidants for the 5-ASA active ingredient of known enema compositions, yet provides for a substantial shelf-life upon prolonged storage.